Generating functionally stable and antigen-specific T _reg cells from effector T cells for cell therapy of inflammatory diseases

One strategy for antigen-specific immunosuppression is to convert antigen-specific conventional T (T conv ) cells into Foxp3 + regulatory T (T reg ) cells that are as stably suppressive as naturally occurring T reg (nT reg ) cells. To achieve the conversion in vitro for mice and humans, we induced high Foxp3 expression in antigen- and interleukin-2 (IL-2)–stimulated T conv cells by CDK8/19 inhibition. We further established T reg cell–specific epigenetic changes by depriving CD28 costimulation during in vitro T reg cell induction to specifically promote the expression of T reg cell signature genes, especially Foxp3 . Repeating this process, with intermittent resting cultures containing IL-2 only, enabled efficient conversion of naïve as well as effector/memory CD4 + T conv cells, including T helper 1 (T H 1), T H 2, and T H 17 cells, into Foxp3 + T reg cells. These induced T reg (iT reg ) cells were similar to nT reg cells in transcription and epigenetic modification and were functionally and phenotypically stable in vivo. Moreover, they effectively suppressed inflammatory bowel disease and graft-versus-host disease in mouse models. Adoptive cell therapy with such effector/memory T conv cell–derived, functionally stable, iT reg cells may represent a strategy to achieve antigen- and disease-specific treatment of immunological diseases.